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Ferulic acid inhibits catamenial epilepsy through modulation of female hormones

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Abstract

Approximately 40% of women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. These seizures result from cyclic changes in circulating progesterone and estradiol levels and there is no effective treatment for this form of intractable epilepsy. We artificially increased progesterone levels and neurosteroid levels (pseudo-pregnancy) in adult Swiss albino female mice (19–23 g) by injecting them with pregnant mares’ serum gonadotropin (5 IU s.c.), followed by human chorionic gonadotropin (5 IU s.c.) after 46 h. After this, ferulic acid (25, 50, 100 mg/kg i.p.) treatment was given for 10 days. During treatment, progesterone, estradiol, and corticosterone levels were estimated in blood on days 1, 5, and 10. Neurosteroid withdrawal was induced by finasteride (50 mg/kg, i.p.) on treatment day 9. Twenty-four hours after finasteride administration (day 10 of treatment), seizure susceptibility was evaluated with the sub-convulsant pentylenetetrazol (PTZ) dose (40 mg/kg i.p.). Four to six hours after PTZ, animals were assessed for depression like phenotypes using tail-suspension test (TST). Four to six hours following TST, animals were euthanized, and discrete brain parts (cortex and hippocampus) were separated for estimation of norepinephrine, serotonin, and dopamine as well as glutamic acid decarboxylase (GAD) enzyme activity. PMSG and HCG treatment elevated progesterone and estradiol levels, assessed on days 1, 5, and 10 causing a state of pseudo-pregnancy. Treatment with finasteride increased seizure susceptibility and depression-like characteristics possibly due to decreased progesterone and elevated estrogen levels coupled with decreased monoamine and elevated corticosterone levels. Ferulic acid treatment, on the other hand, significantly decreased seizure susceptibility and depression like behavior, possibly because of increased progesterone, restored estradiol, corticosterone, monoamines, and GAD enzyme activity. We concluded anticonvulsant effect of ferulic acid in a mouse model of catamenial epilepsy, evidenced by favourable seizure attenuation and curative effect on the circulating progesterone, estradiol, and corticosterone levels along with restorative effect on GAD enzyme activity and monoamine levels.

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Funding

The authors are deeply grateful to the Council of Scientific and Industrial Research (CSIR), Pusa, New Delhi, India for providing financial assistance (Vide F. No. 38 (1339)/12/EMR-II) for the project to Dr. Rajesh Kumar Goel.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, 147002, Patiala, Punjab, India

    Harleen Kaur Dhillon, Tanveer Singh & Rajesh Kumar Goel

  2. Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, College Station, United States of America

    Tanveer Singh

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  1. Harleen Kaur Dhillon
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Contributions

HKD and TS performed experiments. HKD wrote the first draft of manuscript. RKG conceived the idea, edited, and wrote the manuscript.

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Correspondence to Rajesh Kumar Goel.

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The animal experiments were obtained the approval from the Animal Ethics Committee of Punjabi University, India.

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Supplementary Figure. 1

Effect of different treatments on corticosterone, progesterone, and estradiol on day 1, and 5. Each value is expressed as mean ± standard error mean (n = 6). The significance level was considered at P < 0.05 (Student Newman Keuls Post hoc test). *: significant as compared to pseudo pregnant control; # significant as compared to finasteride control; Ω: significant as compared to naïve. Abbreviations: Naïve: saline treatment only; Pseudo: Pseudopregnant control; Fina: Finasteride control; FA 25, 50 and 100: Ferulic acid 25, 50 and 100 mg/kg; i.p.

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Dhillon, H.K., Singh, T. & Goel, R.K. Ferulic acid inhibits catamenial epilepsy through modulation of female hormones. Metab Brain Dis 37, 2827–2838 (2022). https://doi.org/10.1007/s11011-022-01054-w

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